warhead

In a covalent drug, the warhead is the small reactive piece that actually forms the chemical bond with the target. The rest of the molecule is like the guidance and fuselage of a missile, steering it to the right protein and the right spot; the warhead is the tip that detonates on contact, locking the drug onto a nearby reactive amino acid.

A good warhead has to walk a fine line of reactivity. Too sluggish and it never bonds to the target during its short stay; too aggressive and it reacts with the first protein it bumps into anywhere in the body, causing toxicity. Medicinal chemists choose among a toolbox of warhead chemistries — acrylamides and related groups are favorites for snapping onto cysteine residues — and tune them for just enough reactivity. The most common partner is the sulfur atom of a cysteine, which is unusually nucleophilic.

Because the warhead is where the action and the danger both live, much of designing a safe covalent drug is warhead engineering: picking a chemistry that prefers the intended target's residue, and adjusting it so the body can still clear the drug. Note that the same word is used loosely in a different sense for the cytotoxic payload of an antibody-drug conjugate, so context matters.